The long-term goal of these studies is to investigate the effect of genetic and environmental factors on the production and function of human sperm. Mutations that cause spermatogenic arrest and meiotic abnormalities lead to infertility or subfertility. Constitutional chromosome abnormalities such as translocations are of etiologic significance in fetal wastage, still births, and developmental defects. Environmental mutagens and teratogens to which people may be exposed in an industrial or therapeutic context also can have similar effects on fertility and origin of birth defects. Recently, it has become possible to evaluate fertilizability of sperm and to perform karyotypic analysis of sperm chromosomes in an in vitro system. Eggs are collected from superovulated golden hamsters (Mesocricetus auratus) and the zona pellucida removed by slight trypsinization. When such zona-free hamster eggs are mixed with in vitro-capacitated human sperm, the sperm penetrate the eggs. The egg and sperm nuclei develop into pronuclei which can progress to metaphase (hence, the hybrid term, the humster system). The proportion of eggs with decondensed sperm heads (expressed as percentage) is designated the sperm penetration assay (SPA). The latter is generally considered to be an indicator of the penetrability of the given sperm specimen. Colcemid-treatment of penetrated eggs promotes condensation of pronuclei into metaphase plates which can be karyotyped after application of an appropriate banding procedure (e.g. Q-banding). We propose to study, using the humster system, the following groups of men at risk for infertility and generation of chromosomally abnormal sperm due to genetic and environmental causes: (1) men with normal constitutional karyotypes who are infertile, (2) men who are homozygous for rare mutations that cause meiotic disturbances and lead to azoospermia or oligospermia, (3) men who carry chromosome rearrangements, (4) men with Hodgkin's disease who are entered on Memorial Hospital's chemotherapy protocols, (5) men with testicular germ cell tumors who are entered on Memorial Hospital's radiation therapy protocols, and (6) men who have been accidentally or occupationally exposed to clastogens, mutagens, or teratogens. Results of these studies are expected to permit better definition of the genetics of sperm as well as gain insights into the etiology of infertility and birth defects. Techniques for evaluation of SPA as well as analysis of sperm chromosomes are well developed in our laboratory. Our clinical resources (Memorial Hospital and New York Hospital) will ensure the availability of appropriate patient populations for this study.